Enantioselective A³Reactions of Secondary Amines with a Cu(I)/Acid–Thiourea Catalyst Combination

Abstract

Pyrrolidine and related amines undergo asymmetric A(3) reactions in the presence of copper iodide and an easily accessible cocatalyst possessing both a carboxylic acid and a thiourea moiety. Propargylamines are obtained with up to 96% ee, and catalyst loadings can be as low as 1 mol %. Pyrrolidine-derived propargylamines, in the absence of directing groups, can be transformed to the corresponding allenes without loss of enantiopurity.

Recent Advances in the A3 Coupling Reactions and their Applications

“…In 2015, Seidel et al developed a thiourea based chiral ligand 47 for the enantioselective synthesis of propargylamines 46 in the presence of CuI in DCM at 0 °C . The products were obtained in good to excellent yields with high enantioselectivities.…”

Achiral Trisubstituted Thioureas as Secondary Ligands to CuI Catalysts: Direct Catalytic Asymmetric Addition of α‐Fluoronitriles to Imines

“…In marked contrast, Seidel et al. reported improved stereoselectivity with thioureas in Cu I ‐catalyzed enantioselective construction of propargylic amines, in which a beneficial Cu I –thiourea interaction is proposed to occur . Nonetheless, these examples showcase the effect of thiourea co‐catalysts as conventional dual hydrogen‐bond donors.…”

“…The utility of thioureas as ligands in metal‐based catalysis, however, still remains elusive, and there are only a few reports of their application as ligands in transition‐metal‐catalyzed transformations . Intriguingly, in soft Lewis acidic Cu I catalysis, the soft Lewis basic nature of thiourea has diverse effects in modulating Cu I ‐catalyzed transformations . Dixon et al.…”

The Asymmetric A3(Aldehyde–Alkyne–Amine) Coupling: Highly Enantioselective Access to Propargylamines

“…In addition to the use of phosphine-based ligands, Seidel reported the application of carboxylic acid-thiourea as a cocatalyst in Cu(I)-catalyzed asymmetric A 3 reactions with pyrrolidine [69]. A series of urea catalysts were prepared and tested.…”